This invention relates to novel pharmaceutical compositions containing 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-.alpha.,.alph a.-dimethylbenzeneacetates and 1-[p-(2-hydroxymethyl-2-propyl)phenyl]-4-[4-(.alpha.-hydroxy-.alpha.-pheny lbenzyl)-1-piperidinyl]butanol. These compositions possess potent antihistaminic activity and are useful in treating allergic rhinitis, asthma and other allergic disorders while avoiding adverse effects associated with the administration of other .alpha.-aryl-4-substituted piperidinoalkanol derivatives, such as terfenadine, including but not limited to cardiac arrhythmias, drowsiness, nausea, fatigue, weakness and headache. Also, these compositions, in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, are useful for the treatment of cough, cold, cold-like, and/or flu symptoms and the discomfort, headache, pain, fever, and general malaise associated therewith. The aforementioned combinations may optionally include one or more other active components including a decongestant, cough suppressant/antitussive, or expectorant.
Additionally, these novel pharmaceutical compositions containing 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-.alpha.,.alph a.-dimethylbenzeneacetates and 1-[p-(2-hydroxymethyl-2-propyl)phenyl]-4-[4-(.alpha.-hydroxy-.alpha.-pheny lbenzyl)-1-piperidinyl]butanol are useful in treating motion sickness, vertigo, diabetic retinopathy, small vessel complications due to diabetes and such other. conditions as may be related to the activity of these derivatives as antagonists of the H-1 histamine receptor while avoiding the adverse effects associated with the administration of other .alpha.-aryl-4-substituted piperidinoalkanol derivatives, such as terfenadine.
Also disclosed are methods for treating the above-described conditions in a human while avoiding the adverse effects that are associated with the administration of other .alpha.-aryl-4-substituted piperidinoalkanol derivatives, such as terfenadine, by administering the aforementioned pharmaceutical compositions containing 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-.alpha.,.alph a.-dimethylbenzeneacetates and 1-[p-(2-hydroxymethyl-2-propyl)phenyl]-4-[4-(.alpha.-hydroxy-.alpha.-pheny lbenzyl)-1-piperidinyl]butanol to said human.
The active compounds of these compositions and methods are metabolic derivatives of terfenadine. Chemically, these derivatives are methyl 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-.alpha.,.alph a.-dimethylbenzeneacetate, 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-.alpha.,.alph a.-dimethylbenzeneacetic acid, and 1-[p-(2-hydroxymethyl-2-propyl)phenyl]-4-[4-(.alpha.-hydroxy-.alpha.-pheny lbenzyl)-1-piperidinyl]butanol. These compounds are described in Garteiz et al., Arzneimittel-Forschung/Drug Research, 32: 1185-1190 (1982).
Terfenadine is an antagonist of the H-1 histamine receptor protein. Histamine receptor proteins occur in two well-identified forms in tissues as H-1 and H-2 receptors. The H-1 receptors are those that mediate the response antagonized by conventional antihistamines. H-1 receptors are present in the guinea pig ileum, the skin of Rhesus monkeys, and the bronchial smooth muscle of guinea pig. Terfenadine antagonizes the effect of histamine in the guinea pig isolated ileum, suppresses histamine-induced whealing in the skin of Rhesus monkeys, and protects against histamine induced lethality in the guinea pig.
Through H-2 receptor-mediated responses, histamine stimulates gastric acid secretion in the guinea pig and the chronotropic effect in isolated guinea pig atria. Terfenadine has no effect on histamine-induced gastric acid secretion, nor does it alter the chronotropic effect of histamine on atria. Thus, terfenadine has no apparent effect on the H-2 histamine receptor. See Cheng et al., Drug Development Research, 2:181-196 (1982).
Terfenadine is well absorbed but is extensively metabolized. See Okerholm et al., Biopharmaceutics and Drug Distribution, 2:185-190 (1981). Two main metabolites have been identified and one of the metabolites, 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl-1-piperidinyl)butyl]-.alpha.,.alp ha.-dimethylbenzeneacetic acid, is reported to have antihistaminic activity. See Gartiez et al., Arzneimittel-Forschung/Drug Research, 32:1185-1190 (1982).
On the basis of its antihistaminic activity, researchers evaluated the effect of terfenadine in the treatment of allergic rhinitis. Clinical trials of efficacy indicated that terfenadine is slightly less effective than chlorpheniramine, another H-1 antagonist. See Connell, Pharmacotherapy, 5:201-208 (1985).
It has also been suggested that terfenadine would be useful for the treatment of asthma. In guinea pigs, the increase in airway resistance caused by LTD.sub.4 (leukotriene D.sub.4) was suppressed by terfenadine. See Akagi et al., Oyo Yakuri, 35:361-371 (1988).
Terfenadine may also be useful for the treatment of motion sickness and vertigo. Some antihistamines have been found to be effective for the prophylaxis and treatment of motion sickness. See Wood, Drugs, 17:471-479 (1979). Some antihistamines have also proven useful for treating vestibular disturbances, such as Meniere's disease, and in other types of vertigo. See Cohen et al., Archives of Neurology, 27:129-135 (1972).
In addition, terfenadine may be useful in the treatment of diabetic retinopathy and other small vessel disorders associated with diabetes mellitus. In tests on rats with streptozocin-induced diabetes, treatment by antihistamines prevented the activation of retinal histamine receptors which have been implicated in the development of diabetic retinopathy. The use of antihistamines to treat retinopathy and small vessel disorders associated with diabetes mellitus is disclosed in U.S. Pat. No. 5,019,591.
It has also been suggested that terfenadine, in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, would be useful for the treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, headache, fever, and general malaise associated therewith. The use of pharmaceutical compositions containing terfenadine and non-narcotic analgesics or non-steroidal anti-inflammatory agents such as aspirin, acetaminophen, and ibuprofen are described in U.S. Pat. Nos. 4,783,465 and 4,829,064. These compositions for the treatment of the above-described symptoms may optionally include one or more other active components including a decongestant (such as pseudoephedrine), a cough suppressant/antitussive (such as dextromethorphan) or an expectorant (such as guaifenesin).
Many antihistamines cause somewhat similar adverse effects. These adverse effects include but are not limited to sedation, gastrointestinal distress, dry mouth, and constipation or diarrhea. Terfenadine has been found to cause relatively less sedation, gastrointestinal distress, dry mouth, and constipation or diarrhea, as compared with other antihistamines.
However, the administration of terfenadine to a human has been found to cause other adverse effects. These adverse effects include but are not limited to cardiac arrhythmias, including ventricular tachyarrhythmias, torsades de pointes, and ventricular fibrillation. Recently, clinical practitioners have noted an increase in the occurrence of these cardiac arrhythmias upon coadministration of terfenadine with other drugs such as ketoconazole and erythromycin or upon overdose of terfenadine.
Thus, it would be particularly desirable to find a compound with the advantages of terfenadine which would not have the aforementioned disadvantages.